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Abstract

Multiple neurotransmitter systems in the striatum converge to regulate the excitability of striatal neurons by activating several heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs) that signal to the type 5 adenylyl cyclase (AC5), the key effector enzyme that produces the intracellular second messenger cyclic adenosine monophosphate (cAMP). Plasticity of cAMP signaling in the striatum is thought to play an essential role in the development of drug addiction. We showed that the complex of the ninth regulator of G protein signaling (RGS9-2) with the G protein β subunit (Gβ5) critically controlled signaling from dopamine and opioid GPCRs to AC5 in the striatum. RGS9-2/Gβ5 directly interacted with and suppressed the basal activity of AC5. In addition, the RGS9-2/Gβ5 complex attenuated the stimulatory action of Gβγ on AC5 by facilitating the GTPase (guanosine triphosphatase) activity of Gαo, thus promoting the formation of the inactive heterotrimer and inhibiting Gβγ. Furthermore, by increasing the deactivation rate of Gαi, RGS9-2/Gβ5 facilitated the recovery of AC5 from inhibition. Mice lacking RGS9 showed increased cAMP production and, upon withdrawal from opioid administration, enhanced sensitization of AC5. Our findings establish RGS9-2/Gβ5 complexes as regulators of three key aspects of cAMP signaling: basal activity, sensitization, and temporal kinetics of AC5, thus highlighting the role of this complex in regulating both inhibitory and stimulatory GPCRs that shape cAMP signaling in the striatum.